This research has as its focus the coupling of external to cellular respiration during exercise. The ability to perform exercise depends on the dynamic responses of the cardiorespiratory system. These support normal oxygen utilization by the muscle cells, elimination of its CO2 and also acid-base regulation. Recent advances in measurement technology now makes it possible to examine the details of the dynamics of alveolar O2 and CO2 transport in response to exercise. Conceptually there are three functional components of gas exchange dynamics in response to exercise: the cardiodynamic phase (first 25 sec, phase I), the period of increasing O2 extraction and CO2 loading into venous blood (15 sec to approx 3-4 min, phase II), and the period beyond 3-4 min where gas exchange achieves a steady-state below the lactate threshold, but continues to rise above the threshold (phase III). Three major hypotheses will be examined in this project: 1) Alveolar O2 transport dynamics can be used to characterize the state of cardiovascular function during exercise, 2) O2 consumption during heavy work has a component which seems to be linked to mechanisms of lactate metabolism and which causes the O2 cost of the exercise to increase, 3) CO2 output kinetics can be used to measure exercising muscle respiratory quotient and the rate of bicarbonate buffering of metabolic (lactic) acid. For the first hypothesis, we will study normal subjects or patients with particular physiological defects which should interfere with the normal coupling of external to cellular respiration. To test the second hypothesis, we will explore factors which modulate the phase III VO2 during heavy work. To examine the third hypothesis, measurement of lactate, HCO3 and CO2 exchange dynamics in normal subjects will be used as the basis of model analysis of the determinants of CO2 output, both above and below the lactate threshold. These studies utilize the skills of physiologists, physicians, computer scientists and engineers. The time-related changes in O2 uptake and CO2 output in response to exercise are manifestations of specific cardiovascular and metabolic mechanisms. Abnormalities of the response patterns therefore provide important information regarding the site(s) of functional impairment. Understanding these mechanisms is likely to provide the basis for a more rational approach to diagnosis and treatment of patients with exercise limitation.